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DNA methylation inhibits p53-mediated survivin repression

Abstract

The molecular progression of endometrial cancer is poorly understood, and both genetic and epigenetic factors play a role. Survivin is a member of the inhibitor of apoptosis (IAP) gene family and contains a canonical CpG island that has been described as epigenetically regulated. As survivin is overexpressed in endometrial tumors, we hypothesized that hypomethylation could explain this expression pattern. Surprisingly, methylation-specific PCR and pyrosequencing showed that survivin was hypermethylated in endometrial tumors and correlated with increased survivin expression. We speculated that methylation could inhibit the binding of p53, a repressor of survivin expression. Our data indicates that demethylation of the survivin promoter by decitabine results in p53-dependent survivin repression and that p53 binding can be inhibited by DNA methylation. We are the first to report survivin de-repression by DNA methylation. We also present microarray data, which suggest that de-repression by methylation is a general mechanism of p53 regulation. Demethylation induced by decitabine is traditionally thought to be active in tumors by allowing the re-expression of tumor suppressor genes. However, our results indicate that an additional important mechanism is to decrease the expression of oncogenes.

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References

  • Ambrosini G, Adida C, Altieri DC . (1997). A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3: 917–921.

    Article  CAS  PubMed  Google Scholar 

  • Ambrosini G, Adida C, Sirugo G, Altieri DC . (1998). Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J Biol Chem 273: 11177–11182.

    Article  CAS  PubMed  Google Scholar 

  • Campanero MR, Armstrong MI, Flemington EK . (2000). CpG methylation as a mechanism for the regulation of E2F activity. Proc Natl Acad Sci USA 97: 6481–6486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erkanli S, Bolat F, Kayaselcuk F, Demirhan B, Kuscu E . (2007). COX-2 and survivin are overexpressed and positively correlated in endometrial carcinoma. Gynecol Oncol 104: 320–325.

    Article  CAS  PubMed  Google Scholar 

  • Erkanli S, Kayaselcuk F, Kuscu E, Bagis T, Bolat F, Haberal A et al. (2006). Expression of survivin, PTEN and p27 in normal, hyperplastic, and carcinomatous endometrium. Int J Gynecol Cancer 16: 1412–1418.

    Article  CAS  PubMed  Google Scholar 

  • Esteve PO, Chin HG, Pradhan S . (2005). Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. Proc Natl Acad Sci USA 102: 1000–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fukuda S, Pelus LM . (2006). Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther 5: 1087–1098.

    Article  CAS  PubMed  Google Scholar 

  • Furlan D, Carnevali I, Marcomini B, Cerutti R, Dainese E, Capella C et al. (2006). The high frequency of de novo promoter methylation in synchronous primary endometrial and ovarian carcinomas. Clin Cancer Res 12: 3329–3336.

    Article  CAS  PubMed  Google Scholar 

  • Hattori M, Sakamoto H, Satoh K, Yamamoto T . (2001). DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the promoter region of c-erbB-2 and survivin genes. Cancer Lett 169: 155–164.

    Article  CAS  PubMed  Google Scholar 

  • Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M . (2002). Transcriptional repression of the anti-apoptotic survivin gene by wild type p5. J Biol Chem 277: 3247–3257.

    Article  CAS  PubMed  Google Scholar 

  • Hopfer O, Komor M, Koehler IS, Schulze M, Hoelzer D, Thiel E et al. (2007). DNA methylation profiling of myelodysplastic syndrome hematopoietic progenitor cells during in vitro lineage-specific differentiation. Exp Hematol 35: 712–723.

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. (2008). Cancer statistics, 2008. CA Cancer J Clin 58: 71–96.

    Article  PubMed  Google Scholar 

  • Konno R, Yamakawa H, Utsunomiya H, Ito K, Sato S, Yajima A . (2000). Expression of survivin and Bcl-2 in the normal human endometrium. Mol Hum Reprod 6: 529–534.

    Article  CAS  PubMed  Google Scholar 

  • Lehner R, Enomoto T, McGregor JA, Shroyer L, Haugen BR, Pugazhenthi U et al. (2002). Correlation of survivin mRNA detection with histologic diagnosis in normal endometrium and endometrial carcinom. Acta Obstet Gynecol Scand 81: 162–167.

    Article  PubMed  Google Scholar 

  • Li F, Altieri DC . (1999). Transcriptional analysis of human survivin gene expression. Biochem J 344 (Part 2): 305–311.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Meng RD, Phillips P, El-Deiry WS . (1999). p53-independent increase in E2F-1 expression enhances the cytotoxic effects of etoposide and of adriamycin. Int J Oncol 14: 5–14.

    CAS  PubMed  Google Scholar 

  • Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S et al. (2002). Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 21: 2613–2622.

    Article  CAS  PubMed  Google Scholar 

  • Prat J, Gallardo A, Cuatrecasas M, Catasus L . (2007). Endometrial carcinoma: pathology and genetics. Pathology 39: 72–87.

    Article  CAS  PubMed  Google Scholar 

  • Renaud S, Loukinov D, Abdullaev Z, Guilleret I, Bosman FT, Lobanenkov V et al. (2007). Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Nucleic Acids Res 35: 1245–1256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Renaud S, Loukinov D, Bosman FT, Lobanenkov V, Benhattar J . (2005). CTCF binds the proximal exonic region of hTERT and inhibits its transcription. Nucleic Acids Res 33: 6850–6860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shang Y . (2006). Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis. Nat Rev Cancer 6: 360–368.

    Article  CAS  PubMed  Google Scholar 

  • Takai N, Miyazaki T, Nishida M, Nasu K, Miyakawa I . (2002). Survivin expression correlates with clinical stage, histological grade, invasive behavior and survival rate in endometrial carcinoma. Cancer Lett 184: 105–116.

    Article  CAS  PubMed  Google Scholar 

  • Wu H, Chen Y, Liang J, Shi B, Wu G, Zhang Y et al. (2005). Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438: 981–987.

    Article  CAS  PubMed  Google Scholar 

  • Xie R, Loose DS, Shipley GL, Xie S, Bassett Jr RL, Broaddus RR . (2007). Hypomethylation-induced expression of S100A4 in endometrial carcinoma. Mod Pathol 20: 1045–1054.

    Article  CAS  PubMed  Google Scholar 

  • Yoshida H, Broaddus R, Cheng W, Xie S, Naora H . (2006). Deregulation of the HOXA10 homeobox gene in endometrial carcinoma: role in epithelial-mesenchymal transition. Cancer Res 66: 889–897.

    Article  CAS  PubMed  Google Scholar 

  • Zhou XC, Dowdy SC, Podratz KC, Jiang SW . (2007). Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment. Gynecol Oncol 107: 143–153.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Pierre Esteve (New England Biolabs) for generously providing the primer sequences for the Survivin methylation-specific PCR assay, Dr Jean-Pierre Issa and Dr Lanlan Shen (MD Anderson Cancer Center) for designing the survivin pyrosequencing assay and Dr Karen Lu (MD Anderson Cancer Center) and Dr James Pickar (Wyeth Research, Philadelphia, PA, USA) for providing endometrial RNA samples.

This study was supported by Grant NIH 1P50CA098258-01 (SPORE in Endometrial Cancer), and a Rosalie B Hite Graduate Student Fellowship.

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Correspondence to D S Loose.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Nabilsi, N., Broaddus, R. & Loose, D. DNA methylation inhibits p53-mediated survivin repression. Oncogene 28, 2046–2050 (2009). https://doi.org/10.1038/onc.2009.62

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